Quantitative Measurement of Cooperativity in H-Bonded Networks

Cooperative H-bonding interactions are a feature of supramolecular networks involving alcohols. A family of phenol oligomers, in which the hydroxyl groups form intramolecular H-bonds, was used to investigate this phenomenon. Chains of intramolecular H-bonds were characterized using nuclear magnetic resonance (NMR) spectroscopy in solution and X-ray crystallography in the solid state. The phenol oligomers were used to make quantitative measurements of the effects of the intramolecular interactions on the strengths of intermolecular H-bonding interactions between the H-bond donor on the end of the chain and a series of H-bond acceptors. Intramolecular H-bonding interactions in the chain increase the strength of a single intermolecular H-bond between the terminal phenol and quinuclidine by up to 14 kJ mol–1 in the n-octane solution. Although the magnitude of the effect increases with the length of the H-bonded chain, the first intramolecular H-bond has a much larger effect than subsequent interactions. H-bond cooperativity is dominated by pairwise interactions between nearest neighbors, and longer range effects are negligible. The results were used to develop a simple model for cooperativity in H-bond networks using an empirical parameter κ to quantify the sensitivity of the H-bond properties of a functional group to polarization. The value of κ measured in these systems was 0.33, which means that formation of the first H-bond increases the polarity of the next H-bond donor in the chain by 33%. The cumulative cooperative effect in longer H-bonded chains reaches an asymptotic value, which corresponds to a maximum increase in the polarity of the terminal H-bond donor of 50%.


S6
Modified from a previously reported procedure. 2 Solid aluminium chloride (144.7 mg, 1.1 mmol) was added to a solution of 10 (0.5018 g, 1.1 mmol) in dry toluene (14 mL). The reaction mixture was stirred at room temperature for 2 hours under an inert atmosphere. A 10% aqueous solution of hydrochloric acid (10 mL) was added to the reaction mixture and it was extracted with diethyl ether (2x50 mL). The combined organic phases were dried over magnesium sulphate and the solvent was removed reduced pressure. The crude product was purified by flash column chromatography (SiO2, 0-10% gradient of ethyl acetate in petroleum ether). The desired product was obtained as a white solid (121.7 mg, 0.3 mmol, 28%).

S7
Modified from a previously reported procedure. 2 Solid aluminium chloride (850.2 mg, 6.4 mmol) was added to a solution of 2,2'methylenebis(6-tert-butyl-4-methylphenol) 7 (1.0746 g, 3.2 mmol) in dry toluene (32.0 mL). The reaction mixture was stirred for 30 minutes at room temperature under an inert atmosphere. An aqueous solution of hydrochloric acid (1 M, 30 mL) was added. The mixture was extracted with diethyl ether (2x100 mL). The combined organic layers were dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (SiO2, 0-100% gradient of ethyl acetate in petroleum ether). The desired product is a white solid (607.9 mg, 2.7 mmol, 84%).

S9
Modified from a previously reported procedure on a different substrate. 8 To a vigorously stirred solution of 12 (403.9 mg, 1.3 mmol) in methanol (5.0 mL) cooled to 0°C, sodium borohydride (204.2 g, 5.4 mmol) was added. The reaction mixture was then warmed to room temperature and stirred for 1.75 hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolve in ethyl acetate (100 mL) and the organic phase was washed with an aquoues solution of hydrochloric acid 3 M (3x50 mL) and with brine (1x50 mL). The organic phase was dried over magnesium sulphate, filtered and concentrated under reduces pressure. The crude product was purified by flash column chromatography (SiO2, 0-100% gradient of ethyl acetate in petroleum ether). A white solid was obtained as the product (0.3465 g, 1.1 mmol, yield 85%).

X-Ray Crystallography
X-ray data were collected on a Bruker D8-QUEST diffractometer, equipped with an Incoatec IμS Cu microsource (λ = 1.5418 Å) and a PHOTON-III detector operating in shutterless mode. The crystal temperature was held at 180(2) K using an Oxford Cryosystems open-flow N2 Cryostream. The control and processing software was Bruker APEX4 (ver. 2021.4-0). Structures were solved using SHELXT 9 and refined using SHELXL. 10 Analysis of 2 and 3·MeCN was straightforward. Crystals of 3·Quin·CHCl3 were twinned. The diffraction pattern was indexed and integrated as two components related by 180° rotation around the a axis. Refinement was carried out using the HKLF-5 format in SHELXL, including all reflections with a contribution from domain 1. The final refined batch scale factor (0.442 (1)) suggested that the two crystal domains were present in roughly equal proportions.
For all structure refinements, the H atoms associated with the OH groups were located in the difference Fourier map and their positions were refined freely (without O-H distance restraints), with individual isotropic displacement parameters. In each case, the refinements converged to yield satisfactory models, as illustrated below.

Dispersion-corrected density functional theory (DFT-D) calculations for the crystal structures
To support the conclusions on the location of the H atoms in the crystal structures, particularly for the twinned structure of 3·Quin·CHCl3, the crystal structures containing 3 and 4 were energy minimised using periodic dispersion-corrected density functional theory (DFT-D). The calculations were carried out using CASTEP 11 via the interface in Materials Studio (Accelrys, 2012). The PBE exchange-correlation functional was applied, 12 with a dispersion correction according to Grimme. 13 The plane-wave basis-set cut-off was set to 340 eV and all other parameters were set to the "Fine" defaults in Materials Studio. Unit-cell parameters were constrained in each case to those from the reported crystal structure and the space-group symmetry was imposed. For 4, the starting model was taken from the structure available in the Cambridge Structural Database (CUPDUM 14 ). Prior to energy minimisation, the positions of all H atoms were normalised S35 using the default settings in Mercury 15 to produce starting positions close to nuclear positions. For 3·Quin·CHCl3, in which quinuclidine is modelled in two orientations indicative of rotational disorder, only the major component was retained. The energy minimised structures were compared to the starting structures using the method described by van de Streek and Neumann. 16 In each case, the shifts of the non-H atoms on minimisation are in line with expectations for correct crystal structures: To confirm the salt structure as the energy minimum for 3·Quin·CHCl3, the minimisation was carried out using two different starting models: (1) with H3 on N3A, as obtained from the X-ray refinement; (2) with H3 transferred to atom O3 to form a neutral co-crystal. For (2), atom H3 migrated during the optimisation and both starting models converged to the same result in which H3 is bonded to N3A. Atom H2 converges at a position close to halfway between O2 and O3 (closer to O3; see below). The same result is not seen in the minimised structures of 3·MeCN or 4, which include clearly-defined OH groups with O-H distances in the range 1.00-1.02 Å.

H-NMR Titration -General Procedure
Given that the association constant K a for the 1: and [G] can be determined using equation (5) by making iteratively guesses of K a and solving for [G] until the theoretical isotherm matches the experimental data:

UV-Vis Titration -General Procedure
A diluted solution of the host (5 mL) in n-octane is prepared from the stock solution of the receptor in n-octane. 2 mL of the host solution is titrated with a solution of the guest containing also the host at the same concentration in n-octane. A UV-Vis spectrum is recorded for every point of the titration. Analogous to the NMR titrations, equation (6) can be written as where A obs (a.u.) is the observed absorbance, A 0 (a.u.) is the initial absorbance, A f (a.u.) is the final absorbance, K a is the association constant and [G] is the concentration of free guest.
[G] can be determined using equation (7) by making iteratively guesses of K a and solving for [G] until the theoretical isotherm matches the experimental data: (7) where [H] 0 and [G] 0 are the total concentrations of the host and guest, respectively. A Microsoft Excel spreadsheet with purpose-written VBA macros was used to solve equations (6) and (7) fitting the experimentally measured absorbance at specified wavelengths. 17 Each titration was repeated three times, fitted with equations (6) and (7), and an average value of the association constant along with its standard error (with 95% confidence) is reported in table S2.

UV-Vis Dilution -General Procedure
A diluted solution of the host (5 mL) in n-octane is prepared from the stock solution of the receptor in n-octane. Increasing volumes of n-octane were added to 2 mL or 1.5 mL of the host solution. A UV-Vis spectrum is recorded after each addition.

Molecule 1
Dilution Experiment of 1 in n-octane (

Molecule 6
Dilution experiment of 6 in n-octane (

S68
Titrations of 6 with tri-n-octylamine in n-octane Figure S68. (a, c, e) UV-Vis spectra of 6 (0.203 mM) in n-octane at increasing concentrations of tri-noctylamine (from green to red).

Details of computational studies
Molecular mechanics calculations were done using Schrödinger's Maestro software (2019-1 edition), with CHCl3 as the solvent and OPLS 2005 as the force field (charges assigned from the force field, the cut-off was none so that all non-bonded interactions are considered). The minimization method that was used was PRCG (Polak-Ribier Conjugate Gradient) 20 with a maximum iterations number of 10000, the convergence criterion was a gradient with a convergence threshold of 0.01 kJ mol -1 Å -1 . For each conformational search mixed torsional/low mode sampling was used as the method, the maximum number of steps was 10000, the number of structures saved for each search was 50 and the energy window for saving structures was 50.0 kJ/mol.
Starting from the structure with the lowest energy and the desired conformation (i.e. with the intramolecular H-bonds present) calculated with molecular mechanics, all the molecules were footprinted as described previously. 21    Table S3. H-bond donor parameters (α).
The geometry of the structures of 1-4 with the lowest energy and the desired conformation (i.e. with the intramolecular H-bonds present) calculated with molecular mechanics were optimised with Jaguar (functional MO6-2X, basis set 6-31G**, gas phase) followed by a single point energy calculation to compute the values of the Mulliken atomic charges for the terminal hydroxyl protons (Table S4).